DESCRIPTION (Applicant's Description): The candidate, Dr. Dana R. Leach, is applying for a Mentored Clinical Scientist Development Award. Dr. Leach received his D.V.M. degree in 1989 and continued his clinical training at Colorado State University as a resident in anatomic pathology. While at CSU, he also initiated studies involving immunotherapy of tumors. These studies resulted in the award of a Ph.D. degree in the summer of 1995. He is currently working with Dr. James P. Allison in the Cancer Research Laboratory, University of California at Berkeley. Under Dr. Allison's guidance, it is Dr. Leach's goal to expand his studies of basic immunology and the application to tumor therapy and to obtain the necessary training and experience to become a successful independent investigator. The Cancer Research Laboratory, under the direction of Dr. Allison, provides an excellent environment for Dr. Leach's professional development. Dr. Allison is firmly committed to the training of doctoral and postdoctoral personnel and the laboratory has all the necessary resources and equipment for the conduct of the proposed research. The majority of Dr. Leach's efforts will be devoted to this research and related activities. Additionally, his formal training will include participation in the departmental seminars in immunology, basic cell biology and tumor biology, and he will be expected to present his research findings at national meetings. Dr. Leach's research proposal is based on recent findings about the requirements for T cell activation in immune responses. In addition to engagement of the T cell receptor with major histocompatibility complex (MHC) molecules and peptide antigen, other costimulatory signals mediated by cell surface molecules are required. Perhaps the most important costimulatory signals are mediated by the interaction of the B7 family of molecules antigen presenting cells and their ligand, CD28, on T cells. Manipulation of CD28/B7 mediated signals has resulted in enhanced antitumor immunity in a variety of mouse tumor models. CTLA4 is another T cell ligand for B7 molecules, that apparently delivers negative signals involved in the downregulation of T cell responses. Preliminary results show that treatment of mice with a monoclonal antibody directed against CTLA4 results in enhanced antitumor immune responses, possibly by inhibiting the B7/CTLA4 interaction. The experiments proposed in this application are designed to investigate and characterize the antitumor immune response induced in mice treated with anti-CTLA4 antibodies and to explore immunotherapeutic regimens combining different methods of manipulating costimulatory signals to antitumor T cells.